Preparation of a granule containing protein, corn starch and sugar layered on an inert particle

ABSTRACT

Granules that include a protein core are described. The protein core includes a protein matrix which includes a protein mixed together with a starch. The protein matrix can be layered over a seed particle or the protein core can be homogeneous. The protein can be an enzyme or a therapeutic protein.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/180,785,filed Jun. 25, 2002, now U.S. Pat. No. 6,790,643, which is acontinuation of application Ser. No. 09/428,153, filed Oct. 27, 1999,now U.S. Pat. No. 6,413,749, which claims the benefit of U.S.Provisional Application No. 60/105,874, filed Oct. 27, 1998, which isincorporated herein in it entirety.

BACKGROUND OF THE INVENTION

Proteins such as pharmaceutically important proteins like hormones andindustrially important proteins like enzymes are becoming more widelyused. Enzymes are used in several industries including, for example, thestarch industry, the dairy industry, and the detergent industry. It iswell known in the detergent industry that the use of enzymes,particularly proteolytic enzymes, has created industrial hygieneconcerns for detergent factory workers, particularly due to the healthrisks associated with dustiness of the available enzymes.

Since the introduction of enzymes into the detergent business, manydevelopments in the granulation and coating of enzymes have been offeredby the industry.

U.S. Pat. No. 4,106,991 describes an improved formulation of enzymegranules by including within the composition undergoing granulation,finely divided cellulose fibers in an amount of 2-40% w/w based on thedry weight of the whole composition. In addition, this patent describesthat waxy substances can be used to coat the particles of the granulate.

U.S. Pat. No. 4,689,297 describes enzyme containing particles whichcomprise a particulate, water dispersible core which is 150-2,000microns in its longest dimension, a uniform layer of enzyme around thecore particle which amounts to 10%-35% by weight of the weight of thecore particle, and a layer of macro-molecular, film-forming, watersoluble or dispersible coating agent uniformly surrounding the enzymelayer wherein the combination of enzyme and coating agent is from 25-55%of the weight of the core particle. The core material described in thispatent includes clay, a sugar crystal enclosed in layers of corn starchwhich is coated with a layer of dextrin, agglomerated potato starch,particulate salt, agglomerated trisodium citrate, pan crystallized NaClflakes, bentonite granules or prills, granules containing bentonite,kaolin and diatomaceous earth or sodium citrate crystals. The filmforming material may be a fatty acid ester, an alkoxylated alcohol, apolyvinyl alcohol or an ethoxylated alkylphenol.

U.S. Pat. No. 4,740,469 describes an enzyme granular compositionconsisting essentially of from 1-35% by weight of an enzyme and from0.5-30% by weight of a synthetic fibrous material having an averagelength of from 100-500 micron and a fineness in the range of from0.05-0.7 denier, with the balance being an extender or filler. Thegranular composition may further comprise a molten waxy material, suchas polyethylene glycol, and optionally a colorant such as titaniumdioxide.

U.S. Pat. No. 5,324,649 describes enzyme-containing granules having acore, an enzyme layer and an outer coating layer. The enzyme layer and,optionally, the core and outer coating layer contain a vinyl polymer.

WO 91/09941 describes an enzyme containing preparation whereby at least50% of the enzymatic activity is present in the preparation as enzymecrystals. The preparation can be either a slurry or a granulate.

WO 97/12958 discloses a microgranular enzyme composition. The granulesare made by fluid-bed agglomeration which results in granules withnumerous carrier or seed particles coated with enzyme and bound togetherby a binder.

Two of the methods known for preparing granulated enzymes in fluid-bedcoaters include fluid-bed agglomeration and fluid-bed spray-coating. Influid-bed agglomeration, one or more enzymes and a binder are sprayed onto fine powdery carrier solids, which are built up in size byagglomerating together carrier particles. In these agglomerates, thebinder and enzyme serve to bridge multiple carrier particles intogranules of irregular size and shape. In fluid-bed spray-coating, enzymecan be layered onto uniform core particles together with an optionalbinder.

It would be desirable to produce enzyme granules with improvedstability, particularly in bleach-containing detergents at high humidityand temperature. Current fluid-bed spray-coated enzyme granules containthe enzyme in a relatively thin layer near the surface of the granule.This geometry renders the enzyme more vulnerable to being chipped off ofthe granule in a concentrated layer during handling and conveyingoperations, increasing the likelihood and levels of airborne enzymeaerosols in the working environment. This geometry also makes the enzymemore vulnerable to attack by penetrating moisture and inactivatingsubstances.

However, even in light of these developments offered by the industry (asdescribed above) there is a continuing need for low-dust enzyme granuleswhich have additional beneficial characteristics. Additional beneficialcharacteristics needed in the enzyme granulation industry arelow-residue granule formulations (where low residue is defined as areduced tendency to leave noticeable undissolved residues on clothes orother material), and improved stability during storage in, for example,bleach-containing detergent formulas, for example, those containingperoxygen bleaches such as sodium perborate or sodium percarbonate.Accomplishing all these desired characteristics simultaneously is aparticularly challenging task since, for example, many delayed releaseor low-dust agents such as fibrous cellulose or kaolin leave behindinsoluble residues.

As such, there is a need for, for example, a detergent enzyme granulewhich is simultaneously non-dusting, stable when stored in detergents,and easy to manufacture in a controlled size distribution. Granules of acontrolled size distribution are desirable in order to impart goodflowability properties for handling and blending into detergents, and toresist segregation and settling once formulated into detergents. Acontrolled particle size distribution and uniform shape of particles arealso important contributors to achieving a low dust granule.

Therefore, it is an object of the present invention to provide low-dust,low residue, highly soluble enzyme granules having increased stabilityparticularly in bleach-containing detergents. It is another object ofthe present invention to provide processes which afford the formation ofsuch improved granules.

SUMMARY OF THE INVENTION

The present invention provides a granule that includes a protein corethat includes a protein matrix. The protein matrix includes at least oneprotein (e.g., one or more enzymes) mixed together with a starch.Optionally, a barrier layer can be layered over the protein core or abarrier material can be included in the protein core. Also, optionally,a coating can be applied over the seed particle, the enzyme matrixand/or the barrier layer.

The present invention further provides a granule that includes a proteincore that includes a protein matrix layered over a seed particle. Theprotein matrix includes at least one protein (e.g., one or more enzymes)mixed together with a starch. Optionally, a barrier layer can be layeredover the enzyme core or a barrier material can be included in the enzymecore. Also, optionally, a coating can be applied over the seed particle,the enzyme matrix and/or the barrier layer.

The present invention also provides a granule that includes an enzymecore that includes an enzyme matrix. The enzyme matrix includes one ormore enzymes mixed together with a starch. Optionally, a barrier layercan be layered over the enzyme core or a barrier material can beincluded in the enzyme core. Also, optionally, a coating can be appliedover the seed particle, the enzyme matrix and/or the barrier layer.

The present invention additionally provides a granule that includes anenzyme core that includes an enzyme matrix layered over a seed particle.The enzyme matrix includes one or more enzymes mixed together with astarch. Optionally, a barrier layer can be layered over the enzyme coreor a barrier material can be included in the enzyme core. Also,optionally, a coating can be applied over the seed particle, the enzymematrix and/or the barrier layer.

The other features, aspects and advantages of the present invention willbecome apparent from the following detailed description, in conjunctionwith the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the invention is a granule that includes a proteincore that includes a protein matrix. The protein matrix includes one ormore proteins mixed together with a starch. Optionally, a barrier layercan be layered over the protein core or a barrier material can beincluded in the protein core. Also, optionally, a coating can be appliedover the seed particle, the enzyme matrix and/or the barrier layer.

A further embodiment of the invention is a granule that includes aprotein core that includes a protein matrix layered over a seedparticle. The protein matrix includes one or more proteins mixedtogether with a starch. Optionally, a barrier layer can be layered overthe protein core or a barrier material can be included in the proteincore. Also, optionally, a coating can be applied over the seed particle,the enzyme matrix and/or the barrier layer.

Another embodiment of the invention is a granule that includes an enzymecore that includes an enzyme matrix. The enzyme matrix includes one ormore enzymes mixed together with a starch. Optionally, a barrier layercan be layered over the enzyme core or a barrier material can beincluded in the enzyme core. Also, optionally, a coating can be appliedover the seed particle, the enzyme matrix and/or the barrier layer.

A further embodiment of the invention is a granule that includes anenzyme core that includes an enzyme matrix layered over a seed particle.The enzyme matrix includes one or more enzymes mixed together with astarch. Optionally, a barrier layer can be layered over the enzyme coreor a barrier material can be included in the enzyme core. Also,optionally, a coating can be applied over the seed particle, the enzymematrix and/or the barrier layer.

A “protein core”, an “enzyme core” or a “core” includes a proteinmatrix, for example, an enzyme matrix in the case of an enzyme core. Thematrix can be homogenous throughout the core or can be layered over aseed particle. There can be one or more layers between the seed particleand the matrix or the matrix and the barrier layer, for example, acoating such as polyvinyl alcohol (PVA).

Seed particles are inert particles upon which the enzyme matrix can belayered which can be composed, for example, of inorganic salts, sugars,sugar alcohols, small organic molecules such as organic acids or salts,minerals such as clays or silicates or a combination of two or more ofthese. Suitable soluble ingredients for incorporation into seedparticles include: sodium chloride, potassium chloride, ammoniumsulfate, sodium sulfate, sodium sesquicarbonate, urea, citric acid,citrate, sorbitol, mannitol, oleate, sucrose, lactose and the like.Soluble ingredients can be combined with dispersible ingredients such astalc, kaolin or bentonite. Seed particles can be fabricated by a varietyof granulation techniques including: crystallization, precipitation,pan-coating, fluid-bed coating, fluid-bed agglomeration, rotaryatomization, extrusion, prilling, spheronization, drum granulation andhigh shear agglomeration. In the granules of the present invention, if aseed particle is used then the ratio of seed particles to granules is1:1.

The “protein matrix”, “enzyme matrix” or “matrix” is an admixture of oneor more proteins such as an enzyme and a starch. Optionally, the matrixcan include a sugar, such as sucrose. The selected components can bemixed, for example, in solution or as a slurry. The protein can beapplied from a solution or applied in slurry form as a suspension ofcrystals or precipitated protein. The matrix of the present inventioncomprises between about 20-80% of the weight of the granule.

By burying a protein within a matrix, the protein can be betterprotected from the twin dangers of attrition and activity loss. Also, toachieve a low dusting granular protein product, it is necessary tocontrol the shape and size distribution of the granules. Uniform andreproducible size and shape also contribute to granule stability, sinceparticle breakup and re-agglomeration would bring some protein near thegranule surface.

Surprisingly, it has been found that by combining a starch with aprotein, the protein can be applied uniformly to individual seedparticles at rapid rates without agglomeration or attrition. Theresulting particle size distribution can be precisely controlled, basedon knowledge of the starting seed size distribution and the amount ofsolids to be added. The resulting particles are approximately sphericalin shape, have high cohesive strength, and are resistant to attritionand penetration by moisture and inactivating substances.

Starches have high water solubility or dispersibility. A matrix formulacan be easily prepared which includes starches and enzymes as a solutionor slurry with high total solids concentration. Total solution or slurrysolids concentrations of 20-50% w/w or more can be formulated. Theseconcentrated mixtures are highly desirable in that they can be formedinto granules with a minimal need for evaporating water, an advantage inany granulation and drying process.

Proteins that are within the scope of the present invention includepharmaceutically important proteins such as hormones or othertherapeutic proteins and industrially important proteins such asenzymes.

Any enzyme or combination of enzymes may be used in the presentinvention. Preferred enzymes include those enzymes capable ofhydrolyzing substrates, e.g. stains. These enzymes are known ashydrolases which include, but are not limited to, proteases (bacterial,fungal, acid, neutral or alkaline), amylases (alpha or beta), lipases,cellulases and mixtures thereof. Particularly preferred enzymes aresubtilisins and cellulases. Most preferred are subtilisins such asdescribed in U.S. Pat. No. 4,760,025, EP Patent 130 756 B1 and EP PatentApplication WO 91/06637, which are incorporated herein by reference, andcellulases such as Multifect L250™ and Puradax™, commercially availablefrom Genencor International. Other enzymes that can be used in thepresent invention include oxidases, transferases, dehydratases,reductases, hemicellulases and isomerases.

The matrix of the granules of the present invention may further compriseone or more synthetic polymers or other excipients as known to thoseskilled in the art. Suitable synthetic polymers include polyethyleneoxide, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol andpolyethylene oxide/polypropylene oxide.

The matrix may also further comprise plasticizers and anti-agglomerationagents. Suitable plasticizers useful in the present invention includepolyols such as glycerol, propylene glycol, polyethylene glycol (PEG),urea, or other known plasticizers such as triethyl citrate, dibutyl ordimethyl phthalate or water. Suitable anti-agglomeration agents includefine insoluble or sparingly soluble materials such as talc, TiO₂, clays,amorphous silica, magnesium stearate, stearic acid and calciumcarbonate.

The granules of the present invention can further comprise a barrierlayer. A barrier layer is used to slow or prevent the diffusion ofsubstances that can adversely affect the protein or enzyme into thematrix. The barrier layer is made up of a barrier material and can becoated over the protein core or the barrier material can be included inthe protein core. Suitable barrier materials include, for example,inorganic salts or organic acids or salts.

The granules of the present invention can also comprise one or morecoating layers. For example, such coating layers may be one or moreintermediate coating layers or such coating layers may be one or moreoutside coating layers or a combination thereof. Coating layers mayserve any of a number of functions in a granule composition, dependingon the end use of the enzyme granule. For example, coatings may renderthe enzyme resistant to oxidation by bleach, bring about the desirablerates of dissolution upon introduction of the granule into an aqueousmedium, or provide a barrier against ambient moisture in order toenhance the storage stability of the enzyme and reduce the possibilityof microbial growth within the granule.

Suitable coatings include water soluble or water dispersiblefilm-forming polymers such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cellulose derivatives such as methylcellulose,hydroxypropyl methylcellulose, hydroxycellulose, ethylcellulose,carboxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol,polyethylene oxide, gum arabic, xanthan, carrageenan, chitosan, latexpolymers, and enteric coatings. Furthermore, coating agents may be usedin conjunction with other active agents of the same or differentcategories.

Suitable PVAs for incorporation in the coating layer(s) of the granuleinclude partially hydrolyzed, fully hydrolyzed and intermediatelyhydrolyzed PVAs having low to high degrees of viscosity. Preferably, theouter coating layer comprises partially hydrolyzed PVA having lowviscosity. Other vinyl polymers which may be useful include polyvinylacetate and polyvinyl pyrrolidone. Useful copolymers include, forexample, PVA-methylmethacrylate copolymer and PVP-PVA copolymer.

The coating layers of the present invention may further comprise one ormore of the following: plasticizers, extenders, lubricants, pigments,and optionally additional enzymes. Suitable plasticizers useful in thecoating layers of the present invention are plasticizers including, forexample, polyols such as sugars, sugar alcohols, or polyethylene glycols(PEGs), urea, glycol, propylene glycol or other known plasticizers suchas triethyl citrate, dibutyl or dimethyl phthalate or water. Suitablepigments useful in the coating layers of the present invention include,but are not limited to, finely divided whiteners such as titaniumdioxide or calcium carbonate or colored pigments and dyes or acombination thereof. Preferably such pigments are low residue pigmentsupon dissolution. Suitable extenders include sugars such as sucrose orstarch hydrolysates such as maltodextrin and corn syrup solids, clayssuch as kaolin and bentonite and talc. Suitable lubricants includenonionic surfactants such as Neodol, tallow alcohols, fatty acids, fattyacid salts such as magnesium stearate and fatty acid esters.

Adjunct ingredients may be added to the enzyme granules of the presentinvention. Adjunct ingredients may include: metallic salts;solubilizers; activators; antioxidants; dyes; inhibitors; binders;fragrances; enzyme protecting agents/scavengers such as ammoniumsulfate, ammonium citrate, urea, guanidine hydrochloride, guanidinecarbonate, guanidine sulfamate, thiourea dioxide, monoethanolamine,diethanolamine, triethanolamine, amino acids such as glycine, sodiumglutamate and the like, proteins such as bovine serum albumin, caseinand, the like etc., surfactants including anionic surfactants,ampholytic surfactants, nonionic surfactants, cationic surfactants andlong-chain fatty acid salts; builders; alkalis or inorganicelectrolytes; bleaching agents; bluing agents and fluorescent dyes andwhiteners; and caking inhibitors.

For granules having a matrix that includes, in addition to starch, asugar (such as sucrose), it may be desirable to keep the sugar contentof the matrix very low (e.g., substantially less than the starchcontent). For example, in a particular spray coating process, similar tothat described in the examples below, amylase granules having a 1:1 cornstarch:sucrose matrix were found to be very tacky and had a tendency toagglomerate during the spray cycle. A drastic reduction in the sucrosecontent alleviated the tackiness of the matrix. Accordingly, in certaincircumstances, it is preferred to employ a matrix having a high starchcontent relative to the sucrose content. In one preferred embodiment,the ratio (w/w) of starch to sucrose is much greater than 1:1, e.g., inthe range of about 5:1 to 15:1. For example, the ratio can be about10:1.

In an exemplary formulation, sucrose is present in the matrix in anamount of from about 0.5% (w/w) to about 8% (w/w), relative to the totalweight of the granules; and preferably in an amount of about 2% (w/w).In one particularly preferred embodiment, corn starch is present in thematrix in an amount of about 23% and sucrose is present in the matrix inan amount of about 2% (again, w/w, relative to the total weight of thegranules). The sucrose content of this embodiment can be increased above2%, but preferably should not exceed equal parts of corn starch. Forexample, for every 1% increase of sucrose added to the matrix, an equalamount of corn starch is subtracted from the matrix. Thus, if thesucrose content is increased from 2% up to 5%, the corn starch contentwould be adjusted down from 23% to 20%. In this example, the maximumsucrose content would be 12.5%, equaling the calculated corn starchcontent.

While little or no sugar may be useful in certain circumstances (e.g.,as just discussed), it should be appreciated that other circumstances(e.g., where agglomeration does not present a significant problem) maycall for a higher sugar content in the matrix.

The granules described herein may be made by methods known to thoseskilled in the art of enzyme granulation, including pan-coating,fluid-bed coating, prilling, disc granulation, spray drying, extrusion,centrifugal extrusion, spheronization, drum granulation, high shearagglomeration, or combinations of these techniques.

The following examples are representative and not intended to belimiting. One skilled in the art could choose other enzymes, matrices,seed particles, methods and coating agents based on the teachingsherein.

EXAMPLES Example 1 Pilot Scale Fluid Bed Spray Coating of Amylase/StarchMatrix

26 kg sucrose crystals sieved to between 35 and 50 mesh were chargedinto Deseret 60 fluid bed coater and fluidizer. 15.3 kg of an aqueousamylase solution with 31% total dry solids and 12.5% w/w active amylasewas added to 43.5 kg of an aqueous solution containing 23.5 kg of cornstarch. The combined solution was sprayed onto the sucrose under thefollowing conditions:

Fluid feed rate 0.8 kg/min Atomization pressure 75 psi Inlet airtemperature set point NA Product temperature set point 45° C. Inlet airrate 1300 cfm

The coated particles were then coated with an aqueous solutioncontaining 66.7 kg (40% w/w) of magnesium sulfate heptahydrate. Thiscoating was applied under the following conditions:

Fluid feed rate 1.1 kg/min Atomization pressure 60 psi Inlet airtemperature set point NA Product temperature set point 47° C. Inlet Airrate 1800 cfm

The magnesium sulfate coated particles were then cosmetically coatedwith 92.6 kg of an aqueous solution containing 7.1 kg (6.2% w/w)titanium dioxide, 2.9 kg (2.5% w/w) methylcellulose, 2.9 kg (2.5%)Purecote B790, 1.2 kg (1.5% w/w) Neodol 23/6.5, and 2.0 kg (1.67% w/w)of polyethylene glycol at a MW of 600. The cosmetic coating was appliedunder the following conditions:

Fluid feed rate 0.5 kg/min Atomization pressure 75 psi Inlet airtemperature set point NA Product temperature set point 47° C. Inlet Airrate 1800 cfm

Example 2 Pilot Scale Fluid Bed Spray Coating of Amylase/Sucrose-StarchMatrix

26 kg sucrose crystals sieved to between 35 and 50 mesh were chargedinto Deseret 60 fluid bed coater and fluidizer. 15.3 kg of an aqueousamylase solution with 31% total dry solids and 12.5% w/w active amylasewas added to 59.3 kg of an aqueous solution containing 7.8 kg of sucroseand 23.5 kg of corn starch. The combined solution was sprayed onto thesucrose under the following conditions:

Fluid feed rate 0.8 kg/min Atomization pressure 75 psi Inlet airtemperature set point NA Product temperature set point 45° C. Inlet airrate 1300 cfmThe MgSO4 and cosmetic coating were run exactly as described above inExample 1.

Example 3 Exemplary Amylase Granule Formulations

Two additional Lots, denoted as 39 and 43, were prepared substantiallyin accordance with the just-described procedures. Pertinent aspects ofthe formulations for the granules of Lots 39 and 43 were as follows:

The protein matrix of Lot 39 had a 5000 unit payload (wherein “unit”refers to TAU/g [see, e.g., U.S. Pat. No. 5,364,782]). Corn starch waspresent in the matrix in an amount of about 18.8% (w/w), relative to thetotal weight of the granules. The protein maxtrix of this lot wassubstantially devoid of sucrose. A second layer comprising magnesiumsulfate heptahydrate was coated over the protein matrix, such that 30%of the granular weight was comprised of MgSO₄. 7H2O.

The matrix of Lot 43 had the same payload as in Lot 39. Corn starch waspresent in the matrix in an amount of about 18.8% (w/w), and sucrose waspresent in the matrix in an amount of about 6.2% (w/w), both relative tothe total weight of the granules. As with the granules of Lot 39, asecond layer comprising magnesium sulfate heptahydrate was coated overthe protein matrix, such that 30% of the granular weight was comprisedof MgSO₄. 7H2O.

Example 4 Accelerated Stability Tests Using a Detergent Base

The granules of Example 3 were analyzed to determine their stability inaccelerated stability tests. The methods for these procedures weresubstantially as described in Example 3 of WO 99/32613, incorporatedherein by reference.

As discussed in WO 99/32613, the accelerated stability test is designedto aid in the development and screening of granular formulations, as itprovides an accelerated means of determining relative granule stability.The conditions of the accelerated stability test (AST) are far moresevere than enzyme granules or detergents would encounter in realisticstorage or transport. The AST is a “stress test” designed todiscriminate differences between formulations which would otherwise notbe evident for weeks or months.

The AST results set out in Table 2, below, show the percent activityremaining for each of Lots 39 and 43, over a four day period.

TABLE 2 Percent Activity of the Original Day 0 Day 1.3 Day 4 Lot 39100.0 94.3 89.3 Lot 43 100.0 94.4 86.9

Various other examples and modifications of the foregoing descriptionand examples will be apparent to a person skilled in the art afterreading the disclosure without departing from the spirit and scope ofthe invention, and it is intended that all such examples ormodifications be included within the scope of the appended claims. Allpublications and patents referenced herein are hereby incorporated byreference in their entirety.

1. A method of making a granule comprising the steps of: providing aninert particle; preparing an admixture of protein, corn starch andsugar, a ratio of corn starch to sugar being greater than 1:1; applyinga layer of the admixture to surround the inert particle; and applying abarrier layer to surround the admixture layer.
 2. The method of claim 1further comprising the step of applying a coating layer between theinert particle and the admixture layer.
 3. The method of claim 2 furthercomprising the step of applying an outer coating over the barrier layer.4. The method of claim 1 wherein the step of providing an inert particlefurther comprises charging inert particles into a fluid bed coater. 5.The method of claim 1 wherein the step of applying a layer of theadmixture further comprises spraying the admixture onto the inertparticles in the fluid bed coater.
 6. The method of claim 1 herein thestep of applying the barrier layer further comprises spraying thebarrier layer onto the admixture layer.
 7. The method of claim 3 whereinthe step of applying an outer coating further comprises spraying theouter coating onto the barrier layer.
 8. A method of making a granulecomprising the steps of: a). fluidizing in a fluid bed coater inertparticles selected from inorganic salts, sugars, sugar alcohols, organicacids, organic salts, clays, and silicates; b) spraying an admixture ofprotein, corn starch and sugar having a ratio of corn starch to sugargreater than 1:1 onto the inert particles for a time necessary to forman admixture layer around the inert particles; c) spraying a barriermaterial selected from inorganic salts, organic salts, and organic acidsinto the fluid bed coater to form a barrier layer around the admixturelayer; and d) spraying an outer coating selected from polyvinyl alcohol,polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose,hydroxycellulose, ethylcellulose, carboxymethyl cellulose, hydroxypropylcellulose, polyethylene glycol, polyethylene oxide, chitosan, gumarabic, xanthan, and carrageenan into the fluid bed coater until anouter coating is formed around the barrier layer.
 9. A granule made bythe process of claim 1 wherein the admixture comprises about 20-80% ofthe weight of the granule.
 10. A granule made by the process of claim 8wherein the admixture comprises about 20-80% of the weight of thegranule.
 11. A granule made by the process of claim 1 wherein theadmixture comprises a total solids concentration of 20-50% w/w.
 12. Agranule made by the process of claim 8 wherein the admixture comprises atotal solids concentration of 20-50% w/w.
 13. The method of claim 1further comprising the step of applying an outer coating over thebarrier layer.